Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic. The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. In prior years, we have shown that most of this effect is due to genetic variation in APOL1. A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus. An exome scan has identified several promising candidate loci which we are further characterizing. chip. Our progress during the past year included the following: 1) Showing that APOL1 RNA forms stem loops, with the pathogenic G1 and G2 variants doing this more than the common variant G0. This activates protein kinase R, which results in podocyte damage and glomerulosclerosis in transgenic mice. Ms under review. 2) Showing that APOL1 expresses a novel mRNA isoform, which we have termed B3, and the G2 variant activates the inflammasome more than the G0 variant, resulting in increased IL1b production.